Vascular grafts are medical devices used as an artificial conduit for bodily fluids, usually blood. In hemodialysis, the vascular graft serves as a nonstatic reservoir of blood, where blood is readily accessible to a dialysis machine. The vascular graft serves as a life line, an essential interface between the patient and the dialysis machine. In the treatment of peripheral vascular disease and coronary artery disease, vascular grafts provide an artificial conduit bypassing or replacing diseased blood vessels.
Vascular grafts can be natural or artificial. In coronary artery disease, artificial vascular grafts are rarely used due to a high incidence of thrombosis either within the tubular structure or at the anastamosis site. The current graft material of choice is to use a native blood vessel such as the left internal mammary artery or saphenous vein.
In general, thrombosis is problematic with vascular grafts. Thrombosis or cellular growth is the main cause of stenosis within the internal lumen of the vascular graft. Stenosis can occurs as a result of the body's natural healing mechanism. When a vascular graft is implanted, injury occurs to the arterial or venous system to which the vascular graft is sutured and or attached. The vascular graft is also a foreign body. Through a complex process, smooth muscle cells, endothelial cells etc. migrate onto the internal lumen of the graft. As the smooth muscle cells proliferate, they form a neointimal hyperplasia. Over time the neointimal hyperplasia progresses, causing a reduction in the internal diameter of the internal lumen. Stenosis can also be caused by vascular narrowing.
There have been many attempts to inhibit stenosis and thrombosis. Anticoagulants such as heparin have been tried with little success. Antimicrotubule agents such as paclictaxel and docetaxel are known to inhibit mitosis and hence cellular proliferation. Antiproliferative agents such as cyclophosphamide, mithromycin, and actinomycin-D are known to prevent proliferation of smooth muscle cells. Sirolimus, cyclosporine A, dexamethasone and methyl prednisolone are immunosuppressive agents that have been shown to prevent or retard neointimal hyperplasia.
While drugs can significantly inhibit or prevent the occurrence of stenosis and thrombosis, the continued need for the drugs after a graft has been installed can require the patient to remain in a hospital for extended periods of time. It would be advantageous if these drugs could be released from a biocompatible polymer coating within a graft.
At present, there are many biocompatible polymers. For example, poly(ethylene glycol) (PEG) is a water soluble polymer showing excellent biocompatibility and has been frequently used in biomedical applications. Similarly, polysiloxanes are widely used in the biomedical field and have been the subject of intense study both in the academic field as well as in industry.
Amphiphilic polymer networks have also been identified as potentially useful biomaterials. Amphiphilic polymer networks are co-continuous assemblages of hydrophilic and hydrophobic polymer chains that are able to swell in both hydrophilic solvents (e.g., water) and hydrophobic solvents (e.g., a liquid hydrocarbon). Because these materials swell in water, they generally fall into a class of compounds known as “hydrogels”.
The first amphiphilic membranes for biomaterials were developed over a decade ago. These were networks of hydrophilic polymers with the hydrophobic crosslinking agent, di-methacryl-telechelic polyisobutylene (MA-PIB-MA). Synthesis was accomplished by living carbocationic polymerization, which involves the free radical copolymerization and can use a variety of inexpensive, commercially available monomers, for example, N-dimethylaminoethyl methacrylate and dimethyl acrylamide.
Kennedy, U.S. Pat. No. 4,486,572 discloses the synthesis of styryl-telechelic polyisobutylene and amphiphilic networks comprising the copolymerization product of the styryl-telechelic polyisobutylene with vinyl acetate or N-vinyl-2-pyrollidone. Kennedy, U.S. Pat. No. 4,942,204 discloses an amphiphilic copolymer network swellable in both water and n-heptane but insoluble in either, comprising the reaction product of an acrylate or methacrylate of a dialkylaminoalkyl with a hydrophobic bifunctional acryloyl or methacryloyl capped polyolefin. The preferred embodiment disclosed is an amphiphilic network having been synthesized by the free-radical copolymerization of a linear hydrophobic acrylate (A-PIB-A) or methacrylate capped polyisobutylene (MA-PIB-MA) with 2-(dimethylamino)ethyl methacrylate (DMAEMA). In a continuation-in-part to U.S. Pat. No. 4,942,204, Ivan et al. U.S. Pat. No. 5,073,381 discloses various amphiphilic copolymer networks that are swellable in water and n-heptane that comprise the reaction product of a hydrophobic linear acryloyl- or methacryloyl-capped polyolefin and a hydrophilic polyacrylate or polymethacrylate, such as N,N-dimethylacrylamide (DMAAm) and 2-hydroxyethylmethyl methacrylate (HEMA).
Hirt, U.S. Pat. No. 5,807,944 discloses a copolymer of controlled morphology comprising at least one oxygen permeable polymer segment and at least one ion permeable polymer segment, wherein the oxygen permeable segments and the ion permeable segments are linked together through a non-hydrolysable bond. The oxygen-permeable polymer segments are selected from polysiloxanes, perfluoroalkyl ethers, polysulfones, and other unsaturated polymers. The ion permeable polymers are selected from cyclic imino ethers, vinyl ethers, cyclic ethers, including epoxides, cyclic unsaturated ethers, N-substituted aziridines, beta-lactones, beta-lactanes, ketene acetates, vinyl acetates and phosphoranes.
U.S. application Ser. No. 09/433,660 discloses an amphiphilic network comprising the reaction product of hydrophobic crosslinking agents and hydrophilic monomers wherein the hydrophobic crosslinking agents are telechelic three-arm polyisobutylenes having acrylate or methacrylate end caps and wherein the hydrophilic monomers are acrylate or methacrylate derivatives.